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Scope: The decline in estrogen during menopause contributes to a variety of menopausal symptoms, for which hormone replacement therapy (HRT) has been extensively applied. Regarding side effects and limited effectiveness of HRT for specific individuals, there is a growing interest in safe alternatives such as phytoestrogens which are structurally analogous to estrogens. This study aims to investigate the efficacy of yam and gromwell extracts, rich in bioactive compounds, and the synergistic effect of extracts on symptoms induced by estrogen deficiency in ovariectomized (OVX) mice., Methods and Results: OVX mice receive dietary intervention of either yam, gromwell extract, or their mixture for 14 weeks. Sham-operated mice and E2-injected OVX mice serve as positive controls. Following 14 weeks of oral administration, blood, adipose tissue, vagina, uterus, femurs, and tibias are harvested for further investigation. Consequently, yam and gromwell extracts ameliorate menopausal conditions such as weight gain, glucose intolerance, dyslipidemia, and osteoporosis in estrogen-deficient OVX mice. In addition, the mixture of yam and gromwell extracts synergistically aids in the relief of the indications., Conclusion: These results indicate the potential use of yam and gromwell extracts, as well as their mixture, for the development of healthy functional foods to modulate menopausal symptoms., (© 2024 Wiley‐VCH GmbH.)

Classic hereditary hemochromatosis (HH) is an autosomal recessive iron-overload disorder resulting from loss-of-function mutations of the HFE gene. Patients with HH exhibit excessive hepatic iron accumulation that predisposes these patients to liver disease, including the risk for developing liver cancer. Chronic iron overload also poses a risk for the development of metabolic disorders such as obesity, type 2 diabetes, and insulin resistance. We hypothesized that liraglutide, GLP1 receptor agonist, alters iron metabolism while also reducing body weight and glucose tolerance in a mouse model of HH (global HFE knockout, HFE KO) and diet-induced obesity and glucose intolerance. The total body HFE KO and wild-type control mice were fed high-fat diet for 8 weeks. Mice were subdivided into liraglutide and vehicle-treated groups and received daily subcutaneous administration of the respective treatment once daily for 18 weeks. Liraglutide improved glucose tolerance and hepatic lipid markers and reduced body weight in a mouse model of HH, the HFE KO mouse, similar to wild-type controls. Importantly, our data show that liraglutide alters iron metabolism in HFE KO mice, leading to decreased circulating and stored iron levels in HFE KO mice. These observations highlight the potential that GLP1 receptor agonist could be used to reduce iron overload in addition to reducing body weight and improving glucose regulation in HH patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com. See the journal About page for additional terms.)

Background: Impaired glycemic control and the subsequent development of Cystic fibrosis Related Diabetes (CFRD) are prevalent complications, affecting up to 50 % of adults with cystic fibrosis (CF). CFTR modulator (CFTRm) therapies improve pulmonary functions, reduce exacerbation rates, increase survival in people with CF (pwCF) and appear to have a positive effect on extrapulmonary manifestations, such as nutritional state, improvements in upper respiratory symptoms, and quality of life. Initial findings indicate that CFTRm may have a positive impact on short-term glycemic control; however, long-term effects remain uncertain at present., Methods: In this retrospective study, data were collected and analyzed on 15 pwCF, ages 13-37 years, started on CFTRm therapy. Oral Glucose Tolerance Test (OGTT) results were compared pre- and post-CFTRm therapy., Results: The 120-min OGTT value decreased from 159.7 mg/dL to 130.4 mg/dL post-CFTRm (p = 0.047). The average time elapsed between the two OGTTs was 49.87 months (ranging 9-157 months, median 38 months). Glycemic status improved in six pwCF (two CFRD to normal (NGT)/indeterminate (INDET) glucose tolerance; two impaired glucose tolerance (IGT) to INDET; two INDET to NGT) and worsened in one (IGT to CFRD). Six pwCF and NGT remained stable with no changes in glycemic status throughout the follow-up period., Conclusions: CFTRm therapy may decelerate the glycemic control deterioration in pwCF over an extended period. These findings indicate the need for periodic OGTTs following the initiation of CFTRm therapy to appropriately adjust insulin requirements and prevent hypoglycemia. Further larger cohorts are required to authenticate and substantiate these findings., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The integrated stress response (ISR) is a vital signaling pathway initiated by four kinases, PERK, GCN2, HRI and PKR, that ensure cellular resilience and protect cells from challenges. Here, we investigated whether increasing ISR signaling could rescue diabetes-like phenotypes in a mouse model of diet-induced obesity (DIO). We show that the orally available and clinically approved GCN2 activator halofuginone (HF) can activate the ISR in mouse tissues. We found that daily oral administration of HF increases glucose tolerance whilst reducing weight gain, insulin resistance, and serum insulin in DIO mice. Conversely, the ISR inhibitor GSK2656157, used at low doses to optimize its selectivity, aggravates glucose intolerance in DIO mice. Whilst loss of function mutations in mice and humans have revealed that PERK is the essential ISR kinase that protects from diabetes, our work demonstrates the therapeutic value of increasing ISR signaling by activating the related kinase GCN2 to reduce diabetes phenotypes in a DIO mouse model., (© 2024 MRC Laboratory of Molecular Biology.)

Arsenic is a metalloid found in the environment that causes toxic effects in different organs, mainly the liver. This study aimed to investigate the protective effects of epicatechin (EC), a natural flavonol, on glucose intolerance (GI) and liver toxicity caused by sodium arsenite (SA) in mice. Our findings showed that SA exposure led to the development of GI. Liver tissue damage and decreased pancreatic Langerhans islet size were also observed in this study. Mice exposed to SA exhibited hepatic oxidative damage, indicated by reduced antioxidant markers (such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione), along with elevated levels of thiobarbituric acid reactive substances. SA administration elevated the serum activities of liver enzymes alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. Furthermore, notable increases in the levels of inflammatory and apoptotic markers (Toll-like receptor 4, nuclear factor-kappa B, tumor necrosis factor-α, nitric oxide, B-cell lymphoma-2, and cysteine aspartate-specific protease-3) were observed in the liver. Treatment of SA-exposed mice with EC considerably reversed these biochemical and histological changes. This study demonstrated the beneficial effects of EC in ameliorating SA-induced hyperglycemia and hepatotoxicity due to its ability to enhance the antioxidant system by modulating inflammation and apoptosis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Tipepidine (3-[di-2-thienylmethylene]-1-methylpiperidine) (TP) is a non-narcotic antitussive used in Japan. Recently, the potential application of TP in the treatment of neuropsychiatric disorders, such as depression and attention deficit hyperactivity disorder, has been suggested; however, its functions in energy metabolism are unknown. Here, we demonstrate that TP exhibits a metabolism-improving action. The administration of TP reduced high-fat diet-induced body weight gain in mice and lipid accumulation in the liver and increased the weight of epididymal white adipose tissue (eWAT) in diet-induced obese (DIO) mice. Furthermore, TP inhibited obesity-induced fibrosis in the eWAT. We also found that TP induced AMP-activated protein kinase (AMPK) activation in the eWAT of DIO mice and 3T3-L1 cells. TP-induced AMPK activation was abrogated by the transfection of liver kinase B1 siRNA in 3T3-L1 cells. The metabolic effects of TP were almost equivalent to those of metformin, an AMPK activator that is used as a first-line antidiabetic drug. In summary, TP is a potent AMPK activator, suggesting its novel role as an antidiabetic drug owing to its antifibrotic effect on adipose tissues., (© 2024 Federation of American Societies for Experimental Biology.)

Dysmetabolic states, such as type 2 diabetes (T2D), characterized by insulin resistance (IR), are associated with fatty liver, increased cardiovascular disease (CVD) risk, and decreased functional exercise capacity (FEC). Rosiglitazone (RO) improves exercise capacity and IR in T2D. However, the effects of RO on FEC and other markers of CVD risk in prediabetes are unknown. We hypothesized that insulin sensitization with RO would improve exercise capacity and markers of CVD risk in participants with impaired glucose tolerance (IGT). Exercise performance (peak oxygen consumption and oxygen uptake kinetics), IR (homeostasis model assessment of IR and quantitative insulin sensitivity check index), and surrogate cardiovascular endpoints (coronary artery calcium (CAC) volume and density and C-reactive protein (CRP)) were measured in participants with IGT after 12 and 18 months of RO or placebo (PL). RO did not significantly improve exercise capacity. Glycemic measures and IR were significantly lower in people on RO compared to PL at 18 months. CAC volume progression was not different between PL and RO groups. RO did not improve exercise capacity during an 18-month intervention despite improved IR and glycemia in people with IGT. Future studies should explore why effects on FEC with RO occur in T2D but not IGT. Understanding these questions may help in targeting therapeutic approaches in T2D and IGT., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Excess body fat is a risk factor for metabolic diseases and is a leading preventable cause of morbidity and mortality worldwide. There is a strong need to find new treatments that decrease the burden of obesity and lower the risk of obesity-related comorbidities, including cardiovascular disease and type 2 diabetes. Pharmacologic mitochondrial uncouplers represent a potential treatment for obesity through their ability to increase nutrient oxidation. Herein, we report the in vitro and in vivo characterization of compound SHD865, the first compound to be studied in vivo in a newly discovered class of imidazolopyrazine mitochondrial uncouplers. SHD865 is a derivative of the furazanopyrazine uncoupler BAM15. SHD865 is a milder mitochondrial uncoupler than BAM15 that results in a lower maximal respiration rate. In a mouse model of diet-induced adiposity, 6-week treatment with SHD865 completely restored normal body composition and glucose tolerance to levels like those of chow-fed controls, without altering food intake. SHD865 treatment also corrected liver steatosis and plasma hyperlipidemia to normal levels comparable with chow-fed controls. SHD865 has maximal oral bioavailability in rats and slow clearance in human microsomes and hepatocytes. Collectively, these data identify the potential of imidazolopyrazine mitochondrial uncouplers as drug candidates for the treatment of obesity-related disorders., (© 2024 by the American Diabetes Association.)

Statins are currently the most common cholesterol-lowering drug, but the underlying mechanism of statin-induced hyperglycemia is unclear. To investigate whether the gut microbiome and its metabolites contribute to statin-associated glucose intolerance, we recruited 30 patients with atorvastatin and 10 controls, followed up for 16 weeks, and found a decreased abundance of the genus Clostridium in feces and altered serum and fecal bile acid profiles among patients with atorvastatin therapy. Animal experiments validated that statin could induce glucose intolerance, and transplantation of Clostridium sp. and supplementation of ursodeoxycholic acid (UDCA) could ameliorate statin-induced glucose intolerance. Furthermore, oral UDCA administration in humans alleviated the glucose intolerance without impairing the lipid-lowering effect. Our study demonstrated that the statin-induced hyperglycemic effect was attributed to the Clostridium sp.-bile acids axis and provided important insights into adjuvant therapy of UDCA to lower the adverse risk of statin therapy., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Scope: To analyze the effects of fexaramine (FEX), as an intestinal FXR agonist, on the modulation of the intestinal microbiota and ileum of mice fed a high-fat (HF) diet., Methods and Results: Three-month-old C57Bl/6 male mice are divided into two groups and received a control (C, 10% of energy from lipids) or HF (50% of energy from lipids) diet for 12 weeks. They are subdivided into the C, C + FEX, HF, and HF + FEX groups. FEX is administered (FEX-5 mg kg -1 ) via orogastric gavage for three weeks. Body mass (BM), glucose metabolism, qPCR 16S rRNA gene expression, and ileum gene expression, bile acids (BAs), tight junctions (TJs), and incretin are analyzed. FEX reduces BM and glucose intolerance, reduces plasma lipid concentrations and the Firmicutes/Bacteroidetes ratio, increases the Lactobacillus sp. and Prevotella sp. abundance, and reduces the Escherichia coli abundance. Consequently, the ileal gene expression of Fxr-Fgf15, Tgr5-Glp1, and Cldn-Ocldn-Zo1 is increased, and Tlr4-Il6-Il1beta is decreased., Conclusion: FEX stimulates intestinal FXR and improves dysbiosis, intestinal TJs, and the release of incretins, mitigating glucose intolerance and BM increases induced by an HF diet. However, FEX results in glucose intolerance, insulin resistance, and reduces intestinal TJs in a control group, thus demonstrating limitations to this dietary model., (© 2023 Wiley-VCH GmbH.)

Background: The Acarbose Cardiovascular Evaluation (ACE) trial (ISRCTN91899513) evaluated the alpha-glucosidase inhibitor acarbose, compared with placebo, in 6522 patients with coronary heart disease and impaired glucose tolerance in China and showed a reduced incidence of diabetes. We assessed the within-trial medical resource use and costs, and quality-adjusted life years (QALYs)., Methods: Resource use data were collected prospectively within the ACE trial. Hospitalizations, medications, and outpatient visits were valued using Chinese unit costs. Medication use was measured in drug days, with cardiovascular and diabetes drugs summed across the trial by participant. Health-related quality of life was captured using the EuroQol-5 Dimension-3 Level questionnaire. Regression analyses were used to compare resource use, costs, and QALYs, accounting for regional variation. Costs and QALYs were discounted at 3% yearly., Results: Hospitalizations were 6% higher in the acarbose arm during the trial (rate ratio 1.06, p = .009), but there were no significant differences in total inpatient days (rate ratio 1.04, p = .30). Total costs per participant, including study drug, were significantly higher for acarbose (¥ [Yuan] 56 480, £6213), compared with placebo (¥48 079, £5289; mean ratio 1.18, p < 0.001). QALYs reported by participants in the acarbose arm (3.96 QALYs) were marginally higher than in the placebo arm (3.95 QALYs), but the difference was not statistically significant (0.01 QALYs; p = .58)., Conclusions: Acarbose, compared with placebo, participants cost more due to study drug costs and reported no statistically significant difference in QALYs. These higher within-trial costs could potentially be offset in future by savings from the acarbose-related lower incidence of diabetes., (© 2023 The Authors. Journal of Diabetes published by Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Purpose: To evaluate the effects of chromium (Cr) and magnesium (Mg) ions on metabolic profiles, inflammation, and oxidative stress with impaired glucose tolerance (IGT) and insulin resistance (IR)., Methods: 120 individuals with IGT and IR were randomly divided into four groups treated with (1) chromium, (2) magnesium, (3) chromium and magnesium or (4) placebo. Metabolic and inflammatory indicators were measured at baseline and after 3 months intervention., Results: Comparison among groups showed that fasting plasma glucose (FPG), 2 h post glucose (2hPPG), fasting insulin (FINS) and homeostatic model assessment for insulin resistance (HOMA-IR) in Cr + Mg group were significantly decreased compared with the other three groups ( p < .05), and high density lipoprotein (HDL-c) levels were higher. 8-iso prostaglandin F2 alpha (8-iso-PGF2a) decreased in Cr, Mg, and Cr + Mg groups compared with placebo ( p < .05), and 8-iso-PGF2a decreased in Cr + Mg groups compared with Cr group and Mg groups ( p > .05). Intra-group comparison showed that the levels of FPG, 2hPPG and FINS in Cr + Mg group were significantly decreased after intervention ( p < .05), and FINS in Mg group was significantly decreased ( p < .01). The levels of HDL-c and triacylglycerol (TG) in Cr + Mg group were significantly improved ( p < .05). The level of HDL-c in Mg group was significantly improved compared with baseline ( p < .05). Compared with baseline, high-sensitivity C-reactive protein (hsCRP) levels in Cr + Mg group and Mg group were significantly decreased ( p < .05)., Conclusions: The co-supplementation of Cr and Mg improves glycemic and lipid levels and reduces the inflammatory response and oxidative stress profiles of individuals with impaired glucose tolerance and insulin resistance., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Context: The T4DM study randomized 1007 men with impaired glucose tolerance or newly diagnosed diabetes to testosterone undecanoate (TU, 1000 mg) or matching placebo (P) injections every 12 weeks for 24 months with a lifestyle program with testosterone (T) treatment reducing diabetes diagnosis by 40%., Background: The long-term effects on new diagnosis of diabetes, cardiovascular and prostate disease, sleep apnea, weight maintenance trajectory and androgen dependence were not yet described., Methods: A follow-up email survey after a median of 5.1 years since last injection obtained 599 (59%) completed surveys (316 T, 283 P), with participants in the follow-up survey compared with nonparticipants in 23 anthropometric and demographic variables., Results: Randomization to was TU associated with stronger belief in study benefits during (64% vs 49%, P < .001) but not after the study (44% vs 40%, P = .07); there is high interest in future studies. At T4DM entry, 25% had sleep apnea with a new diagnosis more frequent on TU (3.0% vs 0.4%, P = .03) during, but not after, the study. Poststudy, resuming prescribed T treatment was more frequent among TU-treated men (6% vs 2.8%, P = .03). Five years after cessation of TU treatment there was no difference in self-reported rates of new diagnosis of diabetes, and prostate or cardiovascular disease, nor change in weight maintenance or weight loss behaviors., Conclusion: We conclude that randomized T treatment for 24 months in men with impaired glucose tolerance or new diabetes but without pathological hypogonadism was associated with higher levels of self-reported benefits and diagnosis of sleep apnea during, but not after, the study as well as more frequent prescribed poststudy T treatment consistent with androgen dependence in some men receiving prolonged injectable TU., (© Commonwealth of Australia, 2023.)

Background: Epidemiological studies have shown that exposure to sodium arsenite (NaAsO 2 ) causes diabetes and hepatotoxicity. Metformin (MET), an oral hypoglycemic agent, has long been used in diabetes therapy. In addition, MET has been shown to have hepatoprotective effects. In this study, we investigated the effects of MET on NaAsO 2 -induced hepatotoxicity and glucose intolerance in mice., Methods: Mice were divided into four groups: Groups I and II received distilled water and NaAsO 2 (10 mg/kg, p.o.) for five weeks, respectively. Groups III and IV were treated with NaAsO 2 (10 mg/kg, p.o.) for three weeks, followed by MET (125 and 250 mg/kg, p.o.) for the last two weeks before NaAsO 2 . A glucose tolerance test was performed on day 35. The serum and tissue parameters were also evaluated., Results: Histopathological examination revealed NaAsO 2 -induced liver and pancreatic damage. NaAsO 2 caused hyperglycemia, glucose intolerance, and a significant increase in liver function enzymes. Administration of NaAsO 2 significantly reduced hepatic superoxide dismutase, catalase, glutathione peroxidase, and total thiol levels and increased the content of reactive thiobarbituric acid substances. In addition, it led to an increase in liver nitric oxide levels and protein expression of tumor necrosis factor-α, nuclear factor kappa B, and cysteine-aspartic proteases-3. In contrast, treatment with MET (250 mg/kg) significantly improved NaAsO 2 -induced biochemical and histopathological changes., Conclusion: Our findings suggest that the significant effects of MET against NaAsO 2 -induced hepatotoxicity and glucose intolerance may be exerted via the regulation of oxidative stress, followed by suppression of inflammation and apoptosis., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

This review provides an updated overview of the efficacy and safety of pitavastatin in patients with impaired glucose tolerance (IGT). IGT is a prediabetic state characterized by elevated blood glucose levels that do not meet the criteria for diabetes. The review explores the potential benefits of pitavastatin in reducing cardiovascular risk and improving lipid profiles in individuals with IGT. It also examines the glycemic effects of pitavastatin, including its impact on fasting blood glucose levels, insulin sensitivity, and beta-cell function. The review highlights the need for individualized treatment approaches, taking into account the patient's overall cardiovascular risk profile and glycemic control needs. While pitavastatin has shown modest improvements in glycemic control, it is not a substitute for lifestyle modifications or standard antidiabetic medications. Future directions for research include long-term follow-up studies, mechanistic investigations, and comparative analyses to further understand the glycemic effects of pitavastatin in IGT. Overall, this narrative review provides valuable insights for healthcare professionals involved in the management of individuals with IGT, emphasizing the importance of a comprehensive approach to reduce cardiovascular risk and optimize glycemic control., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Aims: To test, for the first time in latent autoimmune diabetes in adults (LADA), the effects of autoantigen-specific immunotherapy by intralymphatic administration of aluminium-formulated recombinant human glutamic acid decarboxylase 65 (GAD-alum); specifically, to test if this treatment is safe, to test whether it induces a strong immunological response akin to a similar protocol in type 1 diabetes and to look for associations with preserved beta-cell function., Materials and Methods: Three GAD-alum injections, 4 μg each, were administered 1 month apart into an inguinal lymph node in 14 people with newly diagnosed LADA (age 30-62 years) presenting with high levels of antibodies against glutamic acid decarboxylase (GADA). Adverse effects, immunological variables and beta-cell function were monitored, with detailed measurements at 5 and 12 months from baseline., Results: Clinical adverse effects were minor and transient and measured laboratory variables were unaffected. All participants completed the study. Treatment raised levels of GADA, elicited strong effects on reactivity of peripheral blood mononuclear cells to GAD and raised cytokine/chemokine levels. Beta-cell function appeared stable preferentially in the seven participants carrying human leukocyte antigen (HLA) haplotypes DR3DQ2, as assessed by C-peptide glucagon tests (P < 0.05 vs. seven non-carriers)., Conclusion: Intralymphatic treatment with GAD-alum in LADA is without clinical or other safety concerns over a 12-month period. As in a similar protocol used in type 1 diabetes, treatment exerts a strong immunological impact and is compatible with protection of beta-cell function preferentially in HLA-DR3DQ2 LADA patients. These findings pave the way for a randomized controlled trial in this important subgroup of LADA patients., (© 2023 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims/hypothesis: In sub-Saharan Africa (SSA), 5% of adults are living with type 2 diabetes and this is rising sharply, with a greater increase among people with HIV. Evidence on the efficacy of prevention strategies in this cohort is scarce. We conducted a Phase II double-blind placebo-controlled trial that aimed to determine the impact of metformin on blood glucose levels among people with prediabetes (defined as impaired fasting glucose [IFG] and/or impaired glucose tolerance [IGT]) and HIV in SSA., Methods: Adults (≥18 years old) who were stable in HIV care and found to have prediabetes (IFG and/or IGT) and who were attending hospitals in Dar es Salaam, Tanzania, were randomised to receive sustained-release metformin, 2000 mg daily, or matching placebo between 4 November 2019 and 21 July 2020. Randomisation used permuted blocks. Allocation was concealed in the trial database and made visible only to the Chief Pharmacist after consent was taken. All participants, research and clinical staff remained blinded to the allocation. Participants were provided with information on diet and lifestyle and had access to various health information following the start of the coronavirus disease 2019 (COVID-19) pandemic. Participants were followed up for 12 months. The primary outcome measure was capillary blood glucose measured 2 h following a 75 g glucose load. Analyses were by intention-to-treat., Results: In total, 364 participants (182 in each arm) were randomised to the metformin or placebo group. At enrolment, in the metformin and placebo arms, mean fasting glucose was 6.37 mmol/l (95% CI 6.23, 6.50) and 6.26 mmol/l (95% CI 6.15, 6.36), respectively, and mean 2 h glucose levels following a 75 g oral glucose load were 8.39 mmol/l (95% CI 8.22, 8.56) and 8.24 mmol/l (95% CI 8.07, 8.41), respectively. At the final assessment at 12 months, 145/182 (79.7%) individuals randomised to metformin compared with 158/182 (86.8%) randomised to placebo indicated that they had taken >95% of their medicines in the previous 28 days (p=0.068). At this visit, in the metformin and placebo arms, mean fasting glucose levels were 6.17 mmol/l (95% CI 6.03, 6.30) and 6.30 mmol/l (95% CI 6.18, 6.42), respectively, and mean 2 h glucose levels following a 75 g oral glucose load were 7.88 mmol/l (95% CI 7.65, 8.12) and 7.71 mmol/l (95% CI 7.49, 7.94), respectively. Using a linear mixed model controlling for respective baseline values, the mean difference between the metformin and placebo group (metformin-placebo) was -0.08 mmol/l (95% CI -0.37, 0.20) for fasting glucose and 0.20 mmol/l (95% CI -0.17, 0.58) for glucose levels 2 h post a 75 g glucose load. Weight was significantly lower in the metformin arm than in the placebo arm: using the linear mixed model adjusting for baseline values, the mean difference in weight was -1.47 kg (95% CI -2.58, -0.35). In total, 16/182 (8.8%) individuals had a serious adverse event (Grade 3 or Grade 4 in the Division of Acquired Immunodeficiency Syndrome [DAIDS] adverse event grading table) or died in the metformin arm compared with 18/182 (9.9%) in the placebo arm; these events were either unrelated to or unlikely to be related to the study drugs., Conclusions/interpretation: Blood glucose decreased over time in both the metformin and placebo arms during the trial but did not differ significantly between the arms at 12 months of follow up. Metformin therapy was found to be safe for use in individuals with HIV and prediabetes. A larger trial with longer follow up is needed to establish if metformin can be safely used for the prevention of diabetes in people who have HIV., Trial Registration: The trial is registered on the International Standard Randomised Controlled Trial Number (ISRCTN) registry ( www.isrctn.com/ ), registration number: ISCRTN76157257., Funding: This research was funded by the National Institute for Health Research using UK aid from the UK Government to support global health research., (© 2023. The Author(s).)

Background: Recent studies have suggested that metabolic syndrome (MS) encompasses a group of risk factors for developing chronic kidney disease (CKD). This work aimed to evaluate the antioxidant and anti-inflammatory effects of allicin in the kidney from an experimental model of MS., Methods: Male Wistar rats (220-250 g) were used, and three experimental groups ( n = 6) were formed: control (C), metabolic syndrome (MS), and MS treated with allicin (16 mg/Kg/day, gastric gavage) (MS+A). MS was considered when an increase of 20% in at least three parameters (body weight, systolic blood pressure (SBP), fasting blood glucose (FBG), or dyslipidemia) was observed compared to the C group. After the MS diagnosis, allicin was administered for 30 days., Results: Before the treatment with allicin, the MS group showed more significant body weight gain, increased SBP, and FBG, glucose intolerance, and dyslipidemia. In addition, increased markers of kidney damage in urine and blood. Moreover, the MS increased oxidative stress and inflammation in the kidney compared to group C. The allicin treatment prevented further weight gain, reduced SBP, FBG, glucose intolerance, and dyslipidemia. Also, markers of kidney damage in urine and blood were decreased. Further, the oxidative stress and inflammation were decreased in the renal cortex of the MS+A compared to the MS group., Conclusion: Allicin exerts its beneficial effects on the metabolic syndrome by considerably reducing systemic and renal inflammation as well as the oxidative stress. These effects were mediated through the Nrf2 pathway. The results suggest allicin may be a therapeutic alternative for treating kidney injury induced by the metabolic syndrome risk factors., Competing Interests: The authors declare that they have no competing interests., (© 2023 Arellano Buendia et al.)

Background: Impaired glucose regulation (defined as either impaired glucose tolerance or impaired fasting glucose) is an important risk factor for the development of diabetes. We aimed to evaluate the safety and effectiveness of metformin plus lifestyle intervention compared with lifestyle intervention alone in preventing diabetes in Chinese participants with impaired glucose regulation., Methods: We did a multicentre, open-label, randomised controlled trial at 43 endocrinology departments in general hospitals across China. Eligible participants were individuals with impaired glucose regulation (ie, impaired glucose tolerance or impaired fasting glucose, or both), men or women aged 18-70 years with a BMI of 21-32 kg/m 2 . Eligible participants were randomly assigned (1:1) via a computer-generated randomisation to receive either standard lifestyle intervention alone or metformin (850 mg orally once per day for the first 2 weeks and titrated to 1700 mg orally per day [850 mg twice per day]) plus lifestyle intervention. Block randomisation was used with a block size of four, stratified by glucose status (impaired fasting glucose or impaired glucose tolerance), hypertension, and use of any anti-hypertensive medication. Lifestyle intervention advice was given by investigators at all participating sites. The primary endpoint was the incidence of newly diagnosed diabetes at the end of the 2-year follow-up. Analysis was done using the full analysis set and per-protocol set. This study is registered with ClinicalTrials.gov, number NCT03441750, and is completed., Findings: Between April, 2017, and June, 2019, 3881 individuals were assessed for eligibility, of which 1678 (43·2%) participants were randomly assigned to either the metformin plus lifestyle intervention group (n=831) or the lifestyle intervention alone group (n=847) and received the allocated intervention at least once. During a median follow-up of 2·03 years, the incidence rate of diabetes was 17·27 (95% CI 15·19-19·56) per 100 person-years in the metformin plus lifestyle intervention group and 19·83 (17·67-22·18) per 100 person-years in the lifestyle intervention alone group. The metformin plus lifestyle intervention group showed a 17% lower risk of developing diabetes than the lifestyle intervention alone group (HR 0·83 [95% CI 0·70-0·99]; log-rank p=0·043). A higher proportion of participants in the metformin plus lifestyle intervention group reported adverse events than in the lifestyle intervention alone group, primarily due to more gastrointestinal adverse events. The percentage of participants reporting a serious adverse event was similar in both groups., Interpretation: Metformin plus lifestyle intervention further reduced the risk of developing diabetes than lifestyle intervention alone in Chinese people with impaired glucose regulation, showing additional benefits of combined intervention in preventing progression to diabetes without new safety concerns., Funding: Merck Serono China, an affiliate of Merck KGaA, Darmstadt, Germany., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests All authors except LJ received research support from the Chinese Association of Geriatric Research. LJ served as a consultant and spoke at scientific meetings for Merck Serono China., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Arsenic is a toxic metalloid that increases the risk of hepatotoxicity and hyperglycemia. The objective of the present study was to assess the effect of ferulic acid (FA) in mitigating glucose intolerance and hepatotoxicity caused by sodium arsenite (SA). A total of six groups including control, FA 100 mg/kg, SA 10 mg/kg, and groups that received different doses of FA (10, 30, and 100 mg/kg), respectively just before SA (10 mg/kg) for 28 days were examined. Fasting blood sugar (FBS) and glucose tolerance tests were conducted on the 29th day. On day 30, mice were sacrificed and blood and tissues (liver and pancreas) were collected for further investigations. FA reduced FBS and improved glucose intolerance. Liver function and histopathological studies confirmed that FA preserved the structure of the liver in groups received SA. Furthermore, FA increased antioxidant defense and decreased lipid peroxidation and tumor necrosis factor-alpha level in SA-treated mice. FA, at the doses of 30 and 100 mg/kg, prevented the decrease in the expression of PPAR-γ and GLUT2 proteins in the liver of mice exposed to SA. In conclusion, FA prevented SA-induced glucose intolerance and hepatotoxicity by reducing oxidative stress, inflammation, and hepatic overexpression of PPAR-γ and GLUT2 proteins., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mohammad Javad Khodayar reports financial support was provided by Ahvaz Jundishapur University of Medical Sciences., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective Graves' disease (GD) is known to cause glucose intolerance. The present study used continuous glucose monitoring (CGM) in 15 patients newly diagnosed with GD to evaluate changes in glucose trends following improvement in the thyroid function. Methods At the time of the diagnosis of GD, each participant wore a CGM monitor for seven days, and the data recorded on days 3 to 5 were analyzed. The clinical status before treatment with antithyroid drugs was evaluated. Following successful treatment with antithyroid drugs and improvement of free thyroxine (fT4) to within the normal range, CGM was used again to evaluate the same variables after treatment. Results The primary outcome, the standard deviation (SD) of glucose, improved from a baseline value of 28.9±4.9 to a post-treatment value of 22.2±5.1 mg/dL (p=0.001). Other variables also improved after treatment, including the mean amplitude of glycemic excursion (MAGE), daily average glucose level, nocturnal average glucose level (0:00-05:59), maximum and minimum glucose, percent time with glucose at >140 mg/dL, and percent time with glucose at >180 mg/dL; however, the coefficient of variation (CV) and percent time with glucose at <70 mg/dL did not improve. A univariate analysis showed the significant correlation of the SD with TSH receptor antibody (TRAb) and 1,5-Anhydro-D-Glucitol (1,5-AG). Conclusion Our results showed that CGM-based markers of mean glucose and glucose variability improved with the improvement of the thyroid function in newly diagnosed GD patients treated with antithyroid drugs.

The use of arsenic in arsenic-based pesticides has been common in many countries in the past and today. There is considerable evidence linking arsenic exposure to hepatotoxicity and diabetes. Destructive phenomena such as hepatic oxidative stress and inflammation can interfere with glucose uptake and insulin function. In the present study, the antioxidant, anti-inflammatory, and molecular mechanism of citicoline against sodium arsenite-induced hepatotoxicity and glucose intolerance were investigated in mice. Citicoline improved glucose tolerance impaired by sodium arsenite. Citicoline increased the hepatic activity of catalase, superoxide dismutase, and glutathione peroxidase enzymes. Moreover, we found that citicoline prevents an increase in the levels of thiobarbituric acid reactive substances. Citicoline reduced levels of caspase 3, tumor necrosis factor-alpha, and interleukin 6 in sodium arsenite intoxicated groups. It was shown that citicoline increased the expression of arsenite methyltransferase, vesicle-associated membrane protein 2, peroxisome proliferator-activated receptor gamma, and sirtuin 3 to combat sodium arsenite toxicity. Citicoline reduced glucose intolerance, which was disrupted by sodium arsenite, by affecting the pancreatic and extra-pancreatic pathways involved in insulin production, secretion, and action. Based on our results, citicoline can be considered a modulating agent against arsenic-induced hepatotoxicity and hyperglycemia. Considering the relationship between arsenic exposure and the occurrence of side effects such as liver toxicity and diabetes, it is necessary to monitor and awareness of arsenic residues from sources such as drinking water., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Accumulating evidence has demonstrated that arcuate nucleus (ARC) of the hypothalamus is likely responsible for the close association between chronic stress, depression, and diabetes. Xiaoyaosan (XYS), a Chinese herbal formula, remarkably improves depressive-like behavior and glucose intolerance, but the mechanism remains unclear. Leptin receptor (LepR) regulates energy expenditure and depression by mediating the action of leptin on the ARC. Therefore, we hypothesized that XYS may regulate depressive-like behavior and glucose intolerance via the leptin and its cascade LepR-STAT3/PI3K pathway in the ARC., Methods: A rat model of depressive-like behavior and susceptibility to glucose intolerance was induced by exposure to chronic unpredictable mild stress (CUMS) for six weeks. XYS (2.224 g/kg) was orally gavaged for six weeks, and fluoxetine (2.0 mg/kg) was administrated to the positive control group. Depressive-like behaviors were assessed using the open field test (OFT), sucrose preference test (SPT) and forced swim test (FST). Fasting blood glucose (FBG) and oral glucose tolerance test (OGTT) were performed to evaluate the effects of XYS on blood glucose. Peripheral leptin and blood lipids were detected using enzyme-linked immunosorbent assay and an automatic biochemical analyzer, respectively. The effects of XYS on the LepR-STAT3/PI3K pathway were detected by quantitative real-time PCR and western blotting., Results: XYS ameliorated CUMS-induced depressive-like behaviors and elevated blood glucose. XYS improved the food intake but have no significant effects on the body weight. Peripheral leptin and its central receptor were also suppressed by XYS, accompanied by the downregulation of JAK2/STAT3 and PI3K/AKT pathway in the ARC. Additionally, XYS increased AGRP and NPY expression but inhibited POMC in the ARC., Conclusions: XYS improves depressive-like behaviors and susceptibility to glucose intolerance induced by CUMS, which may be achieved by the downregulation of the LepR-STAT3/PI3K signaling pathway in the ARC., (© 2023. The Author(s).)

Background: Exogenous glucocorticoids (CGs) possess relevant therapeutic effects but exert diabetogenic actions when in excess. Thus, ligands with potential therapeutic applications and fewer adverse effects are needed. To this, we analyzed whether mometasone furoate (MF), a CG expected to cause fewer side effects, given through systemic routes, could maintain the anti-inflammatory actions without relevant repercussions on metabolism., Methods: The anti-inflammatory effect of MF was evaluated with both peritonitis and colitis models in rodents. Glucose and lipid metabolism were investigated in male and female rats treated daily with MF with different doses and routes of administration for seven days. The involvement of glucocorticoid receptor (GR) on MF actions was assessed in animals pretreated with mifepristone. Also, the potential reversibility of the adverse effects was assessed. Dexamethasone was used as a positive control., Results: MF treatment resulted in glucose intolerance in male rats treated through intraperitoneal (ip) but not oral gavage route (og). In female rats, none of the routes led to glucose intolerance. MF treatment attenuated insulin sensitivity and increased pancreatic β-cell mass, regardless of the sex and route of administration. MF treatment through og route did not result in dyslipidemia, as observed in rats treated through the ip route (both sexes). The anti-inflammatory and metabolic adverse effects of MF were GR-dependent, and metabolic outcomes altered by MF administration were reversible., Conclusion: MF maintains anti-inflammatory activity when administered by systemic routes and exerts less impact on metabolism when administered orally in male and female rats, effects that are GR-dependent and reversible. Category: Metabolic Disorders and Endocrinology., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Nonalcoholic fatty liver disease (NAFLD) which is a leading cause of chronic liver diseases lacks effective treatment. Tamoxifen has been proven to be the first-line chemotherapy for several solid tumors in clinics, however, its therapeutic role in NAFLD has never been elucidated before. In vitro experiments, tamoxifen protected hepatocytes against sodium palmitate-induced lipotoxicity. In male and female mice fed with normal diets, continuous tamoxifen administration inhibited lipid accumulation in liver, and improved glucose and insulin intolerance. Short-term tamoxifen administration largely improved hepatic steatosis and insulin resistance, however, the phenotypes manifesting inflammation and fibrosis remained unchanged in abovementioned models. In addition, mRNA expressions of genes related to lipogenesis, inflammation, and fibrosis were downregulated by tamoxifen treatment. Moreover, the therapeutic effect of tamoxifen on NAFLD was not gender or ER dependent, as male and female mice with metabolic disorders shared no difference in response to tamoxifen and ER antagonist (fulvestrant) did not abolish its therapeutic effect as well. Mechanistically, RNA sequence of hepatocytes isolated from fatty liver revealed that JNK/MAPK signaling pathway was inactivated by tamoxifen. Pharmacological JNK activator (anisomycin) partially deprived the therapeutic role of tamoxifen in treating hepatic steatosis, proving tamoxifen improved NAFLD in a JNK/MAPK signaling-dependent manner., (© 2022. The Author(s).)

Prolactin-releasing peptide (PrRP) is an anorexigenic neuropeptide that has potential for the treatment of obesity and its complications. Recently, we designed a palmitoylated PrRP31 analog (palm 11 -PrRP31) that is more stable than the natural peptide and able to act centrally after peripheral administration. This analog acted as an anti-obesity and glucose-lowering agent, attenuating lipogenesis in rats and mice with high-fat (HF) diet-induced obesity. In Wistar Kyoto (WKY) rats fed a HF diet for 52 weeks, we explored glucose intolerance, but also prediabetes, liver steatosis and insulin resistance-related changes, as well as neuroinflammation in the brain. A potential beneficial effect of 6 weeks of treatment with palm 11 -PrRP31 and liraglutide as comparator was investigated. Liver lipid profiles, as well as urinary and plasma metabolomic profiles, were measured by lipidomics and metabolomics, respectively. Old obese WKY rats showed robust glucose intolerance that was attenuated by palm 11 -PrRP31, but not by liraglutide treatment. On the contrary, liraglutide had a beneficial effect on insulin resistance parameters. Despite obesity and prediabetes, WKY rats did not develop steatosis owing to HF diet feeding, even though liver lipogenesis was enhanced. Plasma triglycerides and cholesterol were not increased by HFD feeding, which points to unincreased lipid transport from the liver. The liver lipid profile was significantly altered by a HF diet that remained unaffected by palm 11 -PrRP31 or liraglutide treatment. The HF-diet-fed WKY rats revealed astrogliosis in the brain cortex and hippocampus, which was attenuated by treatment. In conclusion, this study suggested multiple beneficial anti-obesity-related effects of palm 11 -PrRP31 and liraglutide in both the periphery and brain.

Objective: To observe the effect of Danzhi Jiangtang capsule (DJC) on the clinical indexes and vascular endothelial function indexes in patients with impaired glucose tolerance (IGT)., Methods: A total of 106 patients were enrolled and randomly assigned to the treatment group and control group following a four-week washout period. The patients in the control group received a general lifestyle intervention, while those in the treatment group received DJC (2.0 g 3× a day) in conjunction with the intervention given to the control group patients. The physiological and biochemical levels, vascular endothelial function indices, and traditional Chinese medicine (TCM) syndrome ratings of the patients in the two groups were compared after 12 weeks of therapy., Results: In the control group, the diastolic blood pressure (DBP) was significantly improved compared with those before treatment (83.31 ± 6.47 vs. 79.21 ± 6.17, p  < .01) (CI: 1.45, 6.73; Cohen's d : 10.51), as was the case with the nitric oxide (NO) levels and TCM syndrome points (35.71 ± 4.58 vs. 43.96 ± 5.17, 9.57 ± 2.63 vs. 5.38 ± 1.79, p  < .001) (CI: -10.28, -6.24; 3.12, 5.18; Cohen's d : 0.90). In the treatment group, the levels of fasting blood glucose, endothelin and vascular endothelial growth factor were significantly improved compared with control group (4.92 ± 0.21 vs. 5.59 ± 0.31, 59.37 ± 13.25 vs. 72.13 ± 12.37, 19.25 ± 2.80 vs. 26.76 ± 1.88, p  < .001) (CI: 0.55, 0.78; 7.40, 18.13; 6.52, 8.50; Cohen's d : 4.94, 0.41, 1.32), as was the case with 2-h post-load plasma glucose and total cholesterol (TC) (8.33 ± 0.62 vs. 8.89 ± 1.55, 4.61 ± 1.05 vs. 5.22 ± 1.12, p  < .05) (CI: 0.07, 1.07; 0.15, 1.06; Cohen's d : 0.40, 0.51)., Conclusions: Treatment with DJC could significantly improve the physiological and biochemical indicators, vascular endothelial function, and TCM syndrome points of IGT patients, indicating that DJC could be a potential drug to treat patients with IGT of Qi-Yin deficiency type.

Obesity is a multi-factorial metabolic syndrome that increases the risk of cardiovascular diseases, diabetes, and cancer. We recently demonstrated the antiadipogenic efficacy of lutein using a 3 T3-L1 cell culture model. This study aimed to examine the antiobesity efficacy of lutein on high-fat (60% kcal fat) diet-induced C57BL/6J obese mice model. Lutein (300 and 500 μM), Orlistat (30 mg/kg body weight - positive control), and its combination (orlistat, 15 mg/kg body weight+lutein, 300 μM) were administered in high-fat diet (HFD)-fed mice every other day for 24 weeks. The effect on serum and hepatic lipid parameters was estimated using biochemical assay kits. The adipose tissue expression of adipocyte differentiation markers at gene and protein levels was analyzed by RT-PCR and western blotting, respectively. The results showed that lutein administration and drug significantly reduced epididymal and abdominal adipose tissue weights. Further, lutein reduced the serum cholesterol and LDL-C concentration compared to the HFD group. The HFD-induced elevation in the hepatic triglycerides and cholesterol levels were significantly blocked by lutein and its combination with the drug. Similarly, lutein and its drug combination efficiently lowered the HFD-mediated elevated blood glucose levels. Lutein downregulated the expression of CEBP-α, PPAR-γ, and FAS in the epididymal adipose tissue. Thus, supplementation of lutein may control diet-induced obesity and associated complications in the human population., (© 2022 John Wiley & Sons Ltd.)

Previous research showed that canary seed ( Phalaris canariensis L.) peptides (CSP) possess robust in vitro antiobesity properties via inhibition of pancreatic lipase (PL). Nevertheless, no studies have yet explored their antiobesity properties in vivo. Consequently, we investigated the effects of CSP in C57BL/6J mice under a Western diet (WD). Mice were assigned into groups and fed a normal diet (ND) or a WD accompanied by an oral dose of CSP (250 or 500 mg/kg/day), orlistat (40 mg/kg/day), or distilled water. The results showed that consuming CSP can provide metabolic benefits, including preventing weight gain by up to 20%, increasing glucose tolerance, and reducing insulin, leptin, and LDL/VLDL levels in plasma. Conversely, total ghrelin was unaffected by CSP-500, but decreased by CSP-250, and amplified by orlistat. Surprisingly, CSP-250 was more effective in preventing weight gain and promoting satiety than CSP-500. Parallel to this, protein absorption in CSP-500 was decreased, supported by a rise in fecal crude protein (+3.5%). Similarly, fecal fat was increased by orlistat (38%) and was unaffected by CSP-250 (3.0%) and CSP (3.0%), comparatively to WD (2.5%). Despite this, both CSP treatments were equally effective in decreasing hepatic steatosis and avoiding hyperlipidemia. Furthermore, the enzymatic analysis showed that CSP-PL complexes dissociated faster (15 min) than orlistat-PL complexes (41 min). Lastly, CSP did not affect expression of hepatic lipid oxidation genes ACO and PPAR-α, but reduced the expression of the hydrolase gene LPL, and lipogenesis related genes FAS and ACC. Taken together, these results suggest that CSP antiobesity mechanism relies on lipid metabolism retardation to increase fat transit time and subsequently suppress hunger.

Objective: Based on the tandem mass tag (TMT) technique, our study investigated the potential therapeutic targets of Liraglutide (LIRA) on streptozotocin (STZ) induced impaired glucose tolerance (IGT) in rats and discuss the biological mechanism of the drug against IGT., Methods: 10 rats were randomly selected from 31 male wistar rats of specific pathogen free (SPF) grade as control group and fed with conventional chow, offered the remaining rats a high fat and high sugar (HFSD) diet combined with an intraperitoneal injection of STZ to establish the IGT model, and excluded 2 non-model rats. Specifically, the model rats were randomly divided into Model group (n=10) and LIRA group (n=9). In addition, the LIRA group was subcutaneously injected with 0.06 mg/kg LIRA, during which the metabolic parameters including body weight and fasting blood glucose were recorded. After 8 weeks, samples were taken under anesthesia. Then, the cell morphology was observed using HE staining, and immunofluorescence was performed on the pancreatic tissues of the three groups of rats. Besides, the expression of differential proteins in pancreatic tissues of the three groups of rats was determined by the TMT proteomic labeling. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) biological function analysis were performed on the intersection of Model and LIRA differential proteins., Results: LIRA could not only significantly reduce blood glucose levels but also improve islet cell morphology and function in IGT rats. Among the differential proteins between the model group and the blank group, 44 were reversed after LIRA treatment, of which 14 were up-regulated, while 30 were down-regulated, including PPIF, MPRIP, CYP51, TXNL1, BCL-2, etc. (FC>1.1 or<0.909, P <0.05). According to the GO and KEGG analysis results, it was related to biological processes such as fatty acid metabolism and adipocyte generation, which involved multiple signaling pathways regulating the function of islet cells, such as MAPK, PI, Ras, FcγR, and unsaturated fatty acids, and pyruvate metabolism., Conclusion: To sum up, LIRA participated in anti-IGT therapy through regulation of multiple target proteins and biological functions. This study is of great reference for further exploring the mechanism of action of LIRA at the protein level of IGT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Guo, Han, Xu, Chen, Han, Zhao, Li and Lu.)

Recent studies discuss the evidence of lesser degrees of hyperglycemia contribution to cardiovascular disease (CVD) than impaired glucose tolerance. Indeed, the biggest risk for CVD seems to shift to glucose intolerance in humans with insulin resistance. Although there is a connection between abnormal insulin signaling and heart dysfunction in diabetics, there is also a relation between cardiac insulin resistance and aging heart failure (HF). Moreover, studies have revealed that HF is associated with generalized insulin resistance. Recent clinical outcomes parallel to the experimental data undertaken with antihyperglycemic drugs have shown their beneficial effects on the cardiovascular system through a direct effect on the myocardium, beyond their ability to lower blood glucose levels and their receptor-associated actions. In this regard, several new-class drugs, such as glucagon-like peptide 1 receptor agonists (GLP-1Ra) and sodium-glucose cotransport 2 inhibitors (SGLT2i), can improve cardiac health beyond their ability to control glycemia. In recent years, great improvements have been made toward the possibility of direct heart-targeting effects including modulation of the expression of specific cardiac genes in vivo for therapeutic purposes. However, many questions remain unanswered, regarding their therapeutic effects on cardiomyocytes in heart failure, although there are various cellular levels studies with these drugs. There are also some important comparative studies on the role of SGLT2i versus GLP-1Ra in patients with and without CVD as well as with or without hyperglycemia. Here, we sought to summarize and interpret the available evidence from clinical studies focusing on the effects of either GLP-1Ra or SGLT-2i or their combinations on cardiac structure and function. Furthermore, we documented data from experimental studies, at systemic, organ, and cellular levels. Overall, one can summarize that both clinical and experimental data support that either SGLT2i or GLP-1R agonists have similar benefits as cardioprotective agents in patients with or without impaired glucose tolerance., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Aims/hypothesis: Established dysglycaemia (impaired glucose tolerance [IGT] or type 2 diabetes [T2DM]) is a risk factor for further cardiovascular events in patients with coronary artery disease. Sodium-glucose cotransporter 2 inhibitors reduce this risk. The aim of the present investigation was to test the hypothesis that empagliflozin exerts beneficial effects on myocardial function in patients with a recent acute coronary syndrome and newly detected dysglycaemia., Methods: Forty-two patients (mean age 67.5 years, 81 % male) with recent myocardial infarction (n = 36) or unstable angina (n = 6) and newly detected IGT (n = 27) or T2DM (n = 15) were randomised to 25 mg of empagliflozin daily (n = 20) or placebo (n = 22) on top of ongoing therapy. They were investigated with oral glucose tolerance tests, stress-perfusion cardiac magnetic resonance imaging (CMR) and echocardiography at three occasions: before randomisation, after seven months on study drug and three months following cessation of such drug. Primary outcome was a change in left ventricular (LV) end-diastolic volume (LVEDV) and secondary outcomes were a change in a) systolic and diastolic LV function; b) coronary flow reserve; c) myocardial extracellular volume (ECV) in non-infarcted myocardium; d) aortic pulse wave velocity., Results: Empagliflozin induced a significant decrease in fasting and post load glucose (p < 0.05) and body weight (p < 0.01). Empagliflozin did not influence LVEDV, LV systolic or mass indexes, coronary flow reserve, ECV or aortic pulse wave velocity. Echocardiographic indices of LV diastolic function (E/e' and mitral E/A ratio) were not influenced. No safety concerns were identified., Conclusions/interpretation: Empagliflozin had predicted effects on the dysglycaemia but did not influence variables expressing LV function, coronary flow reserve and ECV. An explanation may be that the LV function of the patients was within the normal range., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: To explore the efficacy and safety of tacrolimus (TAC) combined with corticosteroids in patients with idiopathic membranous nephropathy (IMN)., Methods: A literature search was performed using Embase, Cochrane Library and PubMed from inception through May 31, 2021. All randomized controlled trials (RCTs) exploring the efficacy and safety of TAC combined with corticosteroids in IMN patients were included based on the inclusion and exclusion criteria. Data analyses were conducted using RevMan software (version 5.4)., Results: Seven RCTs involving 520 patients were included in this meta-analysis. Compared with control treatment, TAC combined with corticosteroids could significantly increase the complete remission (CR) rate, total remission (TR) rate, and serum albumin levels, as well as decrease the proteinuria levels within 6-month treatment, but the advantage did not persist to 12-month treatment. After 18-month treatment, the effect of TAC combined with corticosteroids on increasing CR rate, TR rate, and serum albumin levels was significantly worse than control treatment. The mean time to remission in TAC combined corticosteroids group was significantly shorter than that in the control group. The relapse rate, no response rate, change in estimate of the glomerular filtration rate (eGFR), and overall incidence of adverse reactions showed no significant difference between TAC combined with corticosteroids group and control group. However, TAC combined with corticosteroids did have a higher risk of hand tremor, nephrotoxicity, and glucose intolerance than control treatment., Conclusion: TAC combined with corticosteroids has a significant therapeutic effect for IMN patients within 1-year treatment, especially in the first 6 months. However, in the longer-term treatment, TAC combined with corticosteroids does not have an advantage. TAC combined with corticosteroids has a higher risk of hand tremor, nephrotoxicity, and glucose intolerance. More high-quality studies are needed to further verify the long-term efficacy and safety of TAC combined with glucocorticoids in IMN patients., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Objectives: We constructed a recombinant oral GLP-1 analogue in Lactococcus lactis (L. lactis) and evaluated its physiological functions., Results: In silico docking suggested the alanine at position 8 substituted with serine (A8SGLP-1) reduced binding of DPP4, which translated to reduced cleavage by DPP4 with minimal changes in stability. This was further confirmed by an in vitro enzymatic assay which showed that A8SGLP-1 significantly increased half-life upon DPP4 treatment. In addition, recombinant L. lactis (LL-A8SGLP-1) demonstrated reduced fat mass with no changes in body weight, significant improvement of random glycemic control and reduced systemic inflammation compared with WT GLP-1 in db/db mice., Conclusion: LL-A8SGLP-1 adopted in live biotherapeutic products reduce blood glucose in db/db mice without affecting its function., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Hepatitis C virus (HCV) eradication through antivirals ameliorates metabolic profiles. The changes in 2-h plasma glucose (2HPG) levels by oral glucose tolerance test (OGTT), in chronic hepatitis C (CHC) patients who receive directly acting antivirals (DAAs) was elusive. Five hundred and thirty-three CHC patients who achieved sustained virological response (SVR, undetectable HCV RNA throughout 3 months after the end-of-treatment) by DAAs were consecutively enrolled. Pre- and posttreatment 2HPG levels and glucose status were compared. The proportion of patients with improved, worsened, and stable 2HPG was 14.4% (n = 77), 18.6% (n = 99), and 67.0% (n = 357), respectively. Compared with patients with worsening 2HPG, those with improved 2HPG had a higher proportion of cirrhosis (45.5% vs. 24.2%, p = 0.004) and higher pretreatment 2HPG levels (175.3 vs. 129.5 mg/dl, p < 0.001). High baseline 2HPG was independently associated with improved 2HPG in multivariate analysis (odds ratio [OR]/CI: 1.05/1.03-1.06, p < 0.001). When baseline 2HPG was not taken into account, cirrhosis was the only factor independently associated with improved 2HPG status (OR/CI: 2.58/1.29-5.15, p = 0.007). Linear regression analysis revealed that factors independently correlated to changes in 2HPG levels were female sex (β: 8.78; 95% CI:2.34, 15.22; p = 0.01), diabetes (β: -27.72; 95% CI: -50.16, -5.28; p = 0.02), liver cirrhosis (β: -8.91; 95% CI: -16.75, -2.20; p = 0.01), and genotype 1 of HCV (β: -0.12; 95% CI: -15.19, -2.43; p = 0.01). 2HPG improved after HCV eradication by DAAs, particularly in cirrhotic patients., (© 2022 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Diabetes is a life-threatening and debilitating disease with pathological hallmarks, including glucose intolerance and insulin resistance. Plant compounds are a source of novel and effective therapeutics, and the flavonoid (-)-epicatechin, common to popular foods worldwide, has been shown to improve carbohydrate metabolism in both clinical studies and preclinical models. We hypothesized that (-)-epicatechin would alleviate thermoneutral housing-induced glucose intolerance. Male rats were housed at either thermoneutral (30 °C) or room temperature (24 °C) for 16 weeks and gavaged with either 1 mg/kg body weight or vehicle for the last 15 days before sacrifice. Rats housed at thermoneutrality had a significantly elevated serum glucose area under the curve (p < 0.05) and reduced glucose-mediated insulin secretion. In contrast, rats at thermoneutrality treated with (-)-epicatechin had improved glucose tolerance and increased insulin secretion (p < 0.05). Insulin tolerance tests revealed no differences in insulin sensitivity in any of the four groups. Pancreatic immunohistochemistry staining showed significantly greater islet insulin positive cells in animals housed at thermoneutrality. In conclusion, (-)-epicatechin improved carbohydrate tolerance via increased insulin secretion in response to glucose challenge without a change in insulin sensitivity., Competing Interests: The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Objective: The extent to which weight loss contributes to increases in insulin sensitivity (IS) and β-cell function after surgical or medical intervention has not been directly compared in individuals with impaired glucose tolerance or newly diagnosed type 2 diabetes., Methods: The Restoring Insulin Secretion (RISE) Study included adults in the Beta-Cell Restoration Through Fat Mitigation Study (n = 88 randomized to laparoscopic gastric banding or metformin [MET]) and the Adult Medication Study (n = 267 randomized to placebo, MET, insulin glargine/MET, or liraglutide + MET [L + M]). IS and β-cell responses were measured at baseline and after 12 months by modeling of oral glucose tolerance tests and during arginine-stimulated hyperglycemic clamps. Linear regression models assessed differences between and within treatments over time., Results: BMI decreased in all treatment groups, except placebo, at 12 months. IS increased in all arms except placebo and was inversely correlated with changes in BMI. L + M was the only treatment arm that enhanced multiple measures of β-cell function independent of weight loss. Insulin secretion decreased in the laparoscopic gastric banding arm proportional to increases in IS, with no net benefit on β-cell function., Conclusions: Reducing demand on the β-cell by improving IS through weight loss does not reverse β-cell dysfunction. L + M was the only treatment that enhanced β-cell function., (© 2022 The Obesity Society.)

Background: Latent Autoimmune Diabetes in Adults (LADA) constitutes around 10% of all diabetes. Many LADA patients gradually lose their insulin secretion and progress to insulin dependency. In a recent trial BALAD (Behandling Av LADa) early insulin treatment compared with sitagliptin failed to preserve insulin secretion, which deteriorated in individuals displaying high levels of antibodies to GAD (GADA). These findings prompted us to evaluate a treatment that directly affects autoimmunity. Intra-lymphatic GAD-alum treatment has shown encouraging results in Type 1 diabetes patients. We therefore tested the feasibility of such therapy in LADA-patients (the GADinLADA pilot study)., Material and Methods: Fourteen GADA-positive (>190 RU/ml), insulin-independent patients 30-70 years old, with LADA diagnosed within < 36 months were included in an open-label feasibility trial. They received an intra-nodal injection of 4 μg GAD-alum at Day 1, 30 and 60 plus oral Vitamin D 2000 U/d from screening 30 days before (Day -30) for 4 months if the vitamin D serum levels were below 100 nmol/L (40 ng/ml). Primary objective is to evaluate safety and feasibility. Mixed Meal Tolerance Test and i.v. Glucagon Stimulation Test at baseline and after 5 and 12 months are used for estimation of beta cell function. Results will be compared with those of the recent BALAD study with comparable patient population. Immunological response is followed., Results: Preliminary results show feasibility and safety, with almost stable beta cell function and metabolic control during follow-up so far (5 months)., Conclusions: Intra-lymphatic GAD-alum treatment is an option to preserve beta cell function in LADA-patients. An ongoing trial in 14 LADA-patients show feasibility and safety. Clinical and immunological responses will determine how to proceed with future trials., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Björklund, Hals, Grill and Ludvigsson.)

Type 2 diabetes mellitus and impaired glucose tolerance (IGT) significantly induce advanced coronary artery disease and systemic atherosclerosis. Thus, type 2 diabetes mellitus and IGT are traditional risk factors of cardiovascular disease. In contrast, acute coronary syndrome is frequently caused by the rupture of coronary atherosclerotic plaques, which reduces patients' quality of life and might result in death. To date, many trials have sought to identify ways to determine the coronary plaque volume and its vulnerability, and many studies have shown that some specific antihyperglycemic agents might prevent coronary or carotid plaque progression, decrease plaque volume, induce plaque stability, and improve clinical outcomes in patients with type 2 diabetes mellitus and IGT. This article reviews the following: (i) the association between coronary or carotid plaques and abnormal glucose tolerance, including type 2 diabetes mellitus; and (ii) the effects of oral antihyperglycemic drugs to improve clinical outcomes and stabilize atherosclerotic plaques in patients with type 2 diabetes mellitus and IGT., (© 2022 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.)

Metformin is a first-line drug for DM2 treatment and prevention, but its complex effect on impaired glucose tolerance (IGT), including its influence on myocardial resistance to ischemia-reperfusion injury, is not completely studied. We aimed to evaluate the influence of metformin on the intestinal microbiota (IM), metabolism, and functional and morphological characteristics of myocardium in rats with IGT. IGT was modelled in SPF Wistar rats with a high-fat diet and streptozotocin and nicotinamide injection. Rats were divided into three groups: IGT (without treatment), IGT MET (metformin therapy), and CRL (without IGT induction and treatment). IGT group was characterized by: higher body weight, increased serum glucose and total cholesterol levels, atherogenic coefficient, impairment in the functional parameters of the isolated heart during perfusion, and larger myocardium infarction (MI) size in comparison with the CRL group. IM of IGT rats differed from that of CRL: an increase of Bacteroides , Acinetobacter , Akkermansia , Roseburia, and a decrease of Lactobacillus genera representation. Metformin therapy led to the diminishing of metabolic syndrome (MS) symptoms, which correlated with IM restoration, especially with the growth of Akkermansia spp. and decline of Roseburia populations and their influence on other members of IM. The obtained results allow us to consider from a new point of view the expediency of probiotic A. muciniphila use for MS treatment.

Statins are a mainstay in reducing cardiovascular disease risk by reducing circulating levels of plasma LDL-C. In this issue of Med, Wilmanski et al. demonstrate how the composition of the gut microbiome influences the pharmacological benefits and risks of statin therapy, an exciting additional step in personalized medicine., Competing Interests: Declaration of interests The authors declare no ongoing financial interests. The authors declare no other competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To assess whether eldecalcitol, an active vitamin D analogue 2 , can reduce the development of type 2 diabetes among adults with impaired glucose tolerance., Design: Double blinded, multicentre, randomised, placebo controlled trial., Setting: Three hospitals in Japan, between June 2013 and August 2019., Participants: People aged 30 years and older who had impaired glucose tolerance defined by using a 75 g oral glucose tolerance test and glycated haemoglobin level., Interventions: Participants were randomised to receive active vitamin D (eldecalcitol 0.75 μg per day; n=630) or matching placebo (n=626) for three years., Main Outcomes: The primary endpoint was incidence of diabetes. Prespecified secondary endpoints were regression to normoglycaemia and incidence of type 2 diabetes after adjustment for confounding factors at baseline. In addition, bone densities and bone and glucose metabolism markers were assessed., Results: Of the 1256 participants, 571 (45.5%) were women and 742 (59.1%) had a family history of type 2 diabetes. The mean age of participants was 61.3 years. The mean serum 25-hydroxyvitamin D concentration at baseline was 20.9 ng/mL (52.2 nmol/L); 548 (43.6%) participants had concentrations below 20 ng/mL (50 nmol/L). During a median follow-up of 2.9 years, 79 (12.5%) of 630 participants in the eldecalcitol group and 89 (14.2%) of 626 in the placebo group developed type 2 diabetes (hazard ratio 0.87, 95% confidence interval 0.67 to 1.17; P=0.39). Regression to normoglycaemia was achieved in 145 (23.0%) of 630 participants in the eldecalcitol group and 126 (20.1%) of 626 in the placebo group (hazard ratio 1.15, 0.93 to 1.41; P=0.21). After adjustment for confounding factors by multivariable fractional polynomial Cox regression analysis, eldecalcitol significantly lowered the development of diabetes (hazard ratio 0.69, 0.51 to 0.95; P=0.020). In addition, eldecalcitol showed its beneficial effect among the participants with the lower level of basal insulin secretion (hazard ratio 0.41, 0.23 to 0.71; P=0.001). During follow-up, bone mineral densities of the lumbar spine and femoral neck and serum osteocalcin concentrations significantly increased with eldecalcitol compared with placebo (all P<0.001). No significant difference in serious adverse events was observed., Conclusions: Although treatment with eldecalcitol did not significantly reduce the incidence of diabetes among people with pre-diabetes, the results suggested the potential for a beneficial effect of eldecalcitol on people with insufficient insulin secretion., Trial Registration: UMIN Clinical Trials Registry UMIN000010758., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support by a grant from the Kitakyushu Medical Association; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Middle-aged and older men with lower testosterone concentrations are more likely to have or to develop metabolic syndrome and type 2 diabetes. Central adiposity is a risk factor for metabolic syndrome and diabetes and predisposes to lower testosterone concentrations. Conversely, testosterone treatment reduces fat mass and insulin resistance. In a randomized controlled trial of 1007 men with either impaired glucose tolerance or newly diagnosed type 2 diabetes, 2 years of testosterone treatment on a background of lifestyle intervention reduced the risk of type 2 diabetes by 40%; this demonstrates the potential utility for testosterone pharmacotherapy to prevent diabetes in men., Competing Interests: Disclosure B.B. Yeap has received speaker honoraria and conference support from Bayer, Lilly, and Besins and research support from Bayer, Lilly, and Lawley Pharmaceuticals and held advisory roles for Lilly, Besins, Ferring, and Lawley. G.A. Wittert has received speaker honoraria from Bayer and Besins and research support from Bayer, Lilly, and Lawley Pharmaceuticals and held an advisory role for Bayer., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Obesity is accompanied by insulin resistance and glucose intolerance, which favor the onset of complications related to oxidative stress. The aim of this study was to investigate the effects and underlying mechanisms of hydroethanolic extract from Siolmatra brasiliensis stems on insulin resistance, glucose intolerance, advanced glycation end product (AGE) formation, and oxidative stress in mice with induced obesity., Methods: C57BL-6 J mice were fed a high-fat diet for 14 weeks and treated with 125 or 250 mg/kg S. brasiliensis extract during the last 7 weeks. The study assessed glucose tolerance and insulin sensitivity, lipid profile, plasma levels of thiobarbituric acid reactive substances (TBARS, biomarkers of oxidative damage), fluorescent AGEs (biomarkers of advanced glycation), and paraoxonase 1 (PON1) activity (antioxidant enzyme). The activities of the antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px) in the liver and kidneys were also investigated., Results: Siolmatra brasiliensis extract had antiobesogenic effects; improved insulin sensitivity and glucose tolerance; decreased the total plasma cholesterol levels; decreased the levels of glycoxidative stress biomarkers, including AGEs (plasma, liver, kidneys) and TBARS (liver, kidneys); and also improved endogenous antioxidant defenses by increasing the activities of PON1 (plasma), SOD (kidneys), CAT (liver, kidneys), and GSH-Px (kidneys)., Conclusion: This study expands on our knowledge about the pharmacological properties of S. brasiliensis and substantiates the potential of this plant species to be used as a complementary therapeutic agent to alleviate the metabolic dysfunctions resulting from dyslipidemia and glycoxidative stress., (Copyright © 2022 Asia Oceania Association for the Study of Obesity. Published by Elsevier Ltd. All rights reserved.)

This study was designed to investigate the effects of polysaccharide-rich red algae ( Gelidium amansii ) hot-water extracts (GHE) on lipid and glucose metabolism in rats with streptozotocin (STZ)/nicotinamide (NA)-induced diabetes. Rats were divided into three groups: NC-normal control group), DM-diabetic group, and DG-diabetic group supplemented with GHE (5%). The experimental diet and drinking water were available ad libitum for 10 weeks. After the 10-week feeding duration, the body weight, liver weight, total adipose tissue weight, and hepatic TBARS and cholesterol levels were significantly increased, and hepatic glycogen content and adipose lipolysis rate were significantly decreased in the DM group, which could be effectively reversed by supplementation of GHE. However, GHE supplementation could not improve the glucose intolerance in DM rats. It was interesting to note that GHE supplementation could decrease the liver glucose-6-phosphotase activity, which was increased in DM rats. Taken together, these results suggested that GHE feeding may ameliorate abnormal hepatic lipid metabolism, but not glucose intolerance, in diabetic rats induced by STZ/NA.

Context: The time course of male reproductive hormone recovery after stopping injectable testosterone undecanoate (TU) treatment is not known., Objective: The aim of this study was to investigate the rate, extent, and determinants of reproductive hormone recovery over 12 months after stopping TU injections., Materials and Methods: Men (n = 303) with glucose intolerance but without pathologic hypogonadism who completed a 2-year placebo (P)-controlled randomized clinical trial of TU treatment were recruited for further 12 months while remaining blinded to treatment. Sex steroids (testosterone (T), dihydrotestosterone, oestradiol, oestrone) by liquid chromatography-mass sprectometry, luteinizing hormone (LH), follicle-stimulating hormone (FSH) and sex hormone-binding globulin (SHBG) by immunoassays and sexual function questionnaires (Psychosexual Diary Questionnaire, International Index of Erectile Function, and short form survey (SF-12)) were measured at entry (3 months after the last injection) and 6, 12, 18, 24, 40, and 52 weeks later., Results: In the nested cohort of TU-treated men, serum T was initially higher but declined at 12 weeks remaining stable thereafter with serum T and SHBG at 11 and 13%, respectively, lower than P-treated men. Similarly, both questionnaires showed initial carry-over higher scores in T-treated men but after 18 weeks showed no difference between T- and P-treated men. Initially, fully suppressed serum LH and FSH recovered slowly towards the participant's own pre-treatment baseline over 12 months since the last injection., Conclusions: After stopping 2 years of 1000 mg injectable TU treatment, full reproductive hormone recovery is slow and progressive over 15 months since the last testosterone injection but may take longer than 12 months to be complete. Persistent proportionate reduction in serum SHBG and T reflects lasting exogenous T effects on hepatic SHBG secretion rather than androgen deficiency.

The NAD-dependent deacetylase SIRT1 improves β cell function. Accordingly, nicotinamide mononucleotide (NMN), the product of the rate-limiting step in NAD synthesis, prevents β cell dysfunction and glucose intolerance in mice fed a high-fat diet. The current study was performed to assess the effects of NMN on β cell dysfunction and glucose intolerance that are caused specifically by increased circulating free fatty acids (FFAs). NMN was intravenously infused, with or without oleate, in C57BL/6J mice over a 48-h-period to elevate intracellular NAD levels and consequently increase SIRT1 activity. Administration of NMN in the context of elevated plasma FFA levels considerably improved glucose tolerance. This was due not only to partial protection from FFA-induced β cell dysfunction but also, unexpectedly, to a significant decrease in insulin clearance. However, in conditions of normal FFA levels, NMN impaired glucose tolerance due to decreased β cell function. The presence of this dual action of NMN suggests caution in its proposed therapeutic use in humans.

Insulin resistance (IR) is a villain role to the pathology of fatty liver diseases implicated in adipose tissue dysfunction, which is characterized by lipid droplets (LDs) accumulation and hypoxia-inducible factor 1α (HIF1α) related macrophage infiltration. HIF1α is required for its lipogenic actions in adipocytes, while and it regulates M1 and M2 polarization features of macrophages. Losartan has been shown to be an insulin sensitizer in obese states, actions involving in HIF1α signaling. However, the exact mechanisms accounting for these effects have not been fully elucidated. Therefore, GTT, ITT, and HOMA-IR were identified losartan alleviated IR signaling in obese mice. This alleviation may through inhibits HIF1α by suppressing STAT3-NF-κB signaling, which, in turn, revealed HIF1α-dependent decreases the angiogenesis pathway in adipose tissue, including regulation of VEGF and TGFβR2 levels. In white adipose tissue, a set of lipogenesis-related genes, Srebp1 , Fas , and Scd-1 were markedly downregulated after losartan intervention, as well as reduced LDs size and LD-associated proteins, perilipin family proteins (PLINs) compared with obese mice. Losartan abolished macrophage infiltration with upregulation of M2 and inhibition of M1 macrophage markers in obese mice. Our data suggest that losartan attenuated obese-induced fatty liver, linked to alleviating inflammation in adipose tissues and a shift in M1/M2 macrophage balance. Furthermore, losartan might improve mitochondria biogenesis by upregulating SIRT1, PGC1α, UCP1, and mRNA of Tfam , Cd137 , Tmem26 , Ucp1 expression in white adipose tissue compared with the obese group. Taken together, losartan may improve IR and adipose dysfunction by inhibiting lipotoxicity and HIF1α pathways.